Anthracene acids and process



United States Patent Ofilce 3,036,116 Patented May 22, 1962 Antibioticsof the general formula in which X represents hydrogen or chlorine, Yrepresents hydrogen orin case X stands for hydrogen-also the hydroxygroup, have gained great importance in pharmacy. Upto the present daythe compounds are prepared by biological processes. The only synthesisof such tetracyclic compounds or such degradation products containingthe tetracyclic ring system has not yet been described.

L Now it has been found that there are obtained in a good yieldcompounds of the general formula Alk o Alk 0 in which X representshydrogen or chlorine, R and R stand for a carboxy or carbalkoxy group (Rmay also stand for hydrogen) and alk represents a lower molecular alkylradical, particularly methyl, by transforming by reduction compounds ofthe general formula CO-A Olllk O Alk in which X has the meaning givenabove and A represents a halogen atom, especially chlorine or bromine,or an O-alkyl group, into alcohols of the general formula II( CHFCl-IzOH Y OAlk OAlk groups being present can be split, if necessary, bytreatment with acids to free 'hydroxyl groups.

The compounds that come into consideration as starting substances andcorrespond to the general formula O Alk O Alk can be obtained bycondensation of meta-methoxy-acetophenone with a succinic acid ester andsubsequent catalytic hydrogenation of the cisortrans(meta-methoxyphenyl) -p-carbalkoxy-va1eric acid, chlorination ofthe same and treatment of the reaction mixture with polyphosphoric acidat an elevated temperature, separation of the cisortrans-8-methoxy-5-chloro-4-methyl-3-carbalkoxy-tetralone, bromination ofthe same and elimination of hydrogen bromide from the compoundsobtained. For the reduction to the corresponding alcohols there aresuitable acid halides as well'as acid esters. As acid halide there ispreferably used the acid bromide and particularly the acid chloride,whereas as esters there come above all into consideration compounds thatare derived from low molecular, aliphatic alcohols containing 1 to4'carbon atoms such as methanol or ethanol. The reduction is carried outwith the use of complex metal hydrides, particularly lithium aluminiumhydride. The transformation of the acid derivatives into the alcohols iscarried out in inert solvents. Preferably there are used others; cyclicethers being also suitable. There may, for example, be mentioned:diethyl ether, dioxane and tetrahydrofurane. Hydrocarbons may also beused as solvents. The reaction temperature is advantageously chosenbetween 20 C. and +50 C.

The alcohols obtained are then transformed in a manner known per se intothe corresponding halides or tosylates. For the preparation ofhydrohalic acid esters there come into consideration the customarilyused agents such as phosphorus trior pentrabromide or also thionylchloride. It is of advantage to add a small amount of pyridine to thereaction mixture. In this reaction stage the reaction temperature shouldnot exceed 50 C. The reaction itself is carried out in the presence ofdiluents. As such there are suitable ethers, hydrocarbons and above alllow molecular aliphatic chlorinated hydrocarbons.

The transformation into the para-toluene-sulfonic acid ester isadvantageously carried out with para-tosyl chloride in absolutepyridine.

In order to come from the two-membered ring system 7 of the naphthalenemolecule to the three-membered ring system of the anthracene it isnecessary to extend the methylene group being present in the form of thehydrohalic acid ester or para-toluene-sulfonic acid ester bycondensation with suitable compounds. As suitable compounds there comeinto consideration carbalkoxy-succinic acid dialkyl esters orcarbalkoxy-methyl-malonic acid dialkyl esters in the form of theiralkali metal compounds. These alkali metal compounds can be prepared bymeans of the free alkali metals, preferably by means of alkali metalhydrides or amides. The reaction is carried out in the presence ofsolvents. There are preferably used inert solvents, above all ether suchas diethyl ether, dioxane, tetrahydrofurane and aromatic hydrocarbonssuch as benzene and the like. However, there may also be used othersolvents such as alcohols. In this case, however, it has to beconsidered that in the presence of alcohols the solvolytic reactiontakes place concurrently whereby the yield deteriorates.

It has been found that the condensation products ob- ,6 V tained arehydrolized relatively diflicultly if in the succinic acid derivative ormalonicacid derivative used for condensation all three carboxyl groupsare esterified with the same alcohol. Theproblem of the partialhydrolysis can be solved, however, in an elegant and simple manner byusing for the condensation ditertiary butyl-mono-ethyl esters of thesuccinic acid derivatives or of malonic acid derivatives. In thecase ofthe partial hydrolysis merely the ethyl ester group is split up to thefree carboxyl group whereas the two tertiary butyl ester changed.

' According to the invention the cyclization of the condensation productto the vanthracene-one derivative is carried out with polyphosphoricacid under mild condigroups remain untion's. When using tertiary butylesters there is no evolu- 7 Example (a) To a solution of 104 grams ofchloro-terranaph thoic acid dimethyl ether methyl ester in one liter ofabsolute ether there are added dropwise, while stirring and cooling withice, 275 cc. of a 1.5 N lithium aluminum hydride solution. When all ofthe solution has been added, the reaction mixture is stirred for another'hour,.the excess of the lithium aluminum hydride is cantiouslydestroyed by means of methanol and the reaction mixture is extracted bymeans ofZ N-hydrochloric 7 acid. The ether solution is diluted with 200cc. of chlor0- tion of isobutylene worth mentioning. Consequently, the

dilute sodium hydroxide. solution, to the corresponding dicarboxylicacid. The partial hydrolysis to the monocarboxylic acid dicarbalkoxyderivative and the decalboxylation are carried out in known manneraccording to the customary methods of working. a

The alkoxy groups being present in the molecule can already becompletely dealkylated at room temperature within a short time byconcentrated mineral acids so that it is possible in this way to obtainthe corresponding dihydroxy compounds in a simple manner. The followingscheme of formulae serves for elucidation of the reactionsequencerdescribed in the example.

form and, after washing with water, and drying over sodium sulfate, thesolvents are completely distilled off.

,The crystalline residue is taken up in 200 cc. of chloroform and 1liter of petroleum ether (boiling point C.) is slowly added to thesolution. The reaction mixture is allowed to stand for several hours andthe reduction product that has crystallized. out is then filtered offwithsuction. The precipitate is washed with a little ether. There arethus obtained 74 grams (=79% of the theoretical yield) of the purechloroterranaphtholdimethyl ether melting at 120 C. a

(b 20 grams of chloro-terranaphthol-dimethyl ether are dissolved in 500cc. of absolute chloroform and 0.2

cc. of pyridine and 2.9 cc. of phosphorus tribromide are added thereto.The mixture is boiled for 2 hours under reflux. After cooling thereaction mixture is washed 'with water, sodium bicarbonate solution andagain with water. The solution is then dried over sodium sulfate and thesolvent is distilled ofi under reduced pressure. The crystalline residuerepresents the chloro-terranaphthyl bromide dimethyl ether. The compoundcan directly be used for further condensation.

(b 85 grams of chloro-terranaphthol-dimethyl other are dissolved in 300cc. of absolute pyridine. grams of paraatosyl chloride are slowly addedto the mass while stirring vigorously and cooling, so that thetemperature does not exceed +5 C. The reaction mixture is then or on, oron. or om 0000113 A onion A 0mm I v 7 cont 00H. oorn can; can, con.

or our a 01 on, i 1 0000mm i on: oooo orn a V ooomonr (d5) 7 V 3 i0000mm). 5 V rn-oooolni ooh, con. 0 cont 00m G1 CH3 00011 QQHI OCH; 0OCH: 005g 0 The products obtained by the process of the presentinvention are valuable intermediate products forsynthesis ofpharmaceutically valuable compounds such as those of i l thetetracycline group.

The following example serves to illustrate the invention but it is notintended'to it thereto:

allowedtostand for 12 hours in a refrigerator. It is diluted with 2liters of chloroform, the pyridine is extracted with ice cold dilutehydrochloric acid and the chloroform solution is washed with sodiumbicarbonate and water. After drying over-sodium sulfate the sol-' ventis distilled off at 40 under reduced pressure.

The crystalline residue represents the tosylate of theohloro-terranaphthol dimethyl ether than can directly be used forcondensation with the sodium carbethoxymethyl-malonic acid ester withoutfurther purification.

(0 100 grams of chloro-terranaphthol-dimethyl ether are transformed withphosphorus tribromide into the bromide as described under (b 120 gramsof carbethoxy-succinic acid diethyl ester are slowly added drop- Wise toa suspension of 20 grams of sodium hydride in 200 cc. of benzene, themixture is stirred at room temperature until the evolution of hydrogenhas ceased (about 3 hours). The solution is decanted from the sodiumhydride, combined with a solution of the terranaphthylbromide dimethylether in 500 cc. of absolute benzene and boiled for 2 hours underreflux. Aftere cooling, the reaction mixture is diluted with 500 cc. ofether, washed with 1 N-hydrochloric acid and water, dried and thesolvent is completely distilled ofi'. The yellow brown residue is mixedwith 100 cc. of methanol and, when the crystallization has set in,allowed to stand for several hours in the deep-freezing refrigerator.The mother liquor is filtered ofi with suction and the filter residue iswashed well with methanol. By concentrating the filtrate a furtherfraction crystallizes out in the deep-freezing refrigerator. There areobtained altogether 135 grams (75% of the theoretical yield) of thedimethyl ether of i the a-(chloroterranaphthyl) -u-carbethoxy-succinicacid diethyl ester melting at 8l-83 C. After repeated recrystallizationfrom methanol the compound has a constant melting point of 8384 C.

(c )(a) 290 grams of malonic acid ditertiary butyl ester are added to asolution of 33.5 grams of sodium in 750 cc. of absolute ethanol. To thismixture there are added dropwise 250 grams of bromoacetic acid ethylester. The reaction mixture is then heated for 15 minutes on the boilingwater bath, diluted with 3 liters of water, the ester is extracted bymeans of ether and the ether solution is distilled after washing withwater and drying over sodium sulfate. There remains an oil that isdistilled under reduced pressure. There are obtained 130 grams of afraction boiling between 161 and 163 C. (14 mm.) that represents thecarbethoxy-methyl-malonic acid ditertiary butyl ester.

(0 (,3) 85 grams of the dimethyl ether of the chloroterranaphthol aretransformed into the bromide or tosylate in the manner described under(b or (b From the bromide or tosylate obtained there is prepared asolution in 400 cc. of absolute benzene.

In addition, there is prepared a solution of sodiumcar-bethoxy-methyl-malonic acid ditertiary butyl ester intetrahydrofurane by slowly adding dropwise 92 grams of the ester into asuspension of 20 grams of sodium hydride in 400 cc. of absolutetetrahydrofurane, stirring the mixture for 3 hours at room temperatureand decanting the solution from the sodium hydride in excess. Thesolution thus obtained is combined with the solution of the bromide ortosylate, the main quantity of the tetrahydrofurane is distilled ofiwith exclusion of humidity and the remaining benzene solution is boiledfor two hours under reflux. After cooling the soluton is washed with iN-hydrochloric acid, dried and freed from the solvent. The hot oilyresidue is taken up in 300 cc. of methanol. The crystallization of thecondensation product sets in after a short time. The whole is allowed tostand for several hours, the crystallisate that has separated isfiltered off with suction and washed with methanol. By concentrating themother liquor there is obtained a second fraction, the mother liquor ofwhich yields a third fraction upon standing in the deep-freezingrefrigerator. The total yield of the condensation product of the formulaI CO 0 C (CH OHr-O-CO O 0 (CH 011200 0 CrHs OCH3 OCH:

amounts to 148 grams (84% of the theoretical yield). A sample of thecompound recrystallized repeatedly from methanol melts at 9495 C.However, the raw product can be subjected without further purificationto the cyclization reaction and partial hydrolysis hereinafterdescribed.

(d 132 grams of the dimethyl ether of theot-(chloroterranaphthyl)-a-carbethoxy-succinic acid diethyl ester areheated to boiling for 35 minutes under reflux with 1.5 liters of anethanolic potassium hydroxide solution of 5% strength. The mixture isthen poured into 2 liters of Water, extracted by means of ether, theaqueous phase is acidified with dilute hydrochloric acid and extractedwith chloroform. The chloroform extract is washed with water, dried andthe solvent is completely distilled oft". The residue is mixed with 150cc. of glacial acetic acid and the solution is stirred for 25 minutes at70 C. with 500 cc. of p'olyphosphoric acid. The mixture is then pouredon ice water. The reaction product is extracted with ether. The extractis freed by filtration from black fiocculant impurities, washed with.sodium carbonate solution and water, dried and finally evaporated.There remain 66 grams of a brown oil that is mixed with cc. of ether.When the crystallization has set in, the mixture is allowed to stand forseveral hours in the deep-freezing refrigerator. The crystals that haveprecipitated are separated from the solution by filtering with suctionand the filter residue is washed well with ether. There are obtained10.2 grams ('=8.5% of the theoretical yield) of the1.2.3.4-tetrahydro-3.3- .dicarbethoxy 9 methyl 5- chloro 8.10dimethoxyanthracene-l-one. The compound melts at l23 C. A samplerecrystallized repeatedly from methanol melts at l24.5l26.5 C.

(d From the filtrate of the product obtained according to (d the solventis completely distilled off. The residue is taken up in benzene and thesolution obtained is filtered through a column of acid silica gel.Benzene is used for the additional washing. The filtrate is completelyevaporated and the oily residue (45 grams) is boiled for 1 hour underreflux with 100 cc. of methanol and 100 cc. of a sodium hydroxidesolution of 10% strength, in which 2 grams of sodium 'dithionite aredissolved. The yellow brown solution is diluted with 500 cc. of waterand acidified. The reaction mixture is allowed to stand for severalhours, the semi-solid precipitate is filtered off with suction andrecrystallized from 50 cc. of glacial acetic acid. The crystallisatethat has separated is filtered ofi'ywith suction after sometime and thefilter residue is washed well with chloroform and ether. There are thusobtained 11.2 gramsof a dicarboxylic acid of the formula OOOH OCH OOH Othat can be worked up without further purification.

The solvent is completely distilled off from the mother liquor, theresidue is taken up in 50 cc. of phthalic acid diethyl ester, and thesolution isheated to 170 C. un-

' jected. From the dark brown zone adhering to the upper part of thecolumn there separates slowly a deep yellow zone that is eluated, aftercutting up the column, by means of a mixture of chloroform and acetonein a proportion of 10:1. The eluate is concentrated, taken up in- 10 cc.of acetone and 150 cc; of

benzene, and the acetone is distilled off 'azeotropic'ally.

After standing for several hours the 1.2.3.4-tetrahydro- 3.3dicarbethoxy 9 methyl S'- chloro 8.10 dimethoxy-anthracene-l-one thathas crystallized out is separated from the mother liquor by filteringwith suction. The filter residue is'washed with ether and dried. Theyield of monocarboxylic acid amounts to 3.6 grams. (d 10.2 grams of1.2.3.4-tetrahydro-3.3-carhethoxy-9- methMS-chIOro-S.IO-dimethoxy-anthracened one (obtained in the manner asdescribed under ((1 are boiled for one hour under reflux With'a mixtureof 75 cc. of methanol and 75 cc. of a sodium hydroxide solu tion of 10%strength containing 2 grams of sodium dithionite in the dissolved state,the solution is diluted 7 with 500cc. of hotwater and the boilingsolution is acidified. After cooling the reaction product that hascrystallized out is filtered off with suction, the filter residue iswashed well with water and dried. The yield of dicar-boxylic acid(formula-see under (d amounts to 8.40 grams (94% of the theoreticalyield). When heated the compound melts between 165 and 170 C. withevolution of carbon dioxide.

,4) The 8.40Qgrarns or 11.2 grams of dicarboxylic acid of the formula pV Cl CH3 i e coon coon OCHaYCH; O 7' obtained by the hydrolysis asdescribed under (ri and (d are suspended in .75 cc. of phthalic aciddiethyl ester. The mixture is heated in an oil bath to 170 C. After theevolution of carbon dioxide has ceased the reaction mixture is dilutedwith 200 cc. of ether and allowed to stand for several hours. Thecrystal magma that has separated is filtered oif with suction andcarefully washediwith ether. The filtrate isexhaustively extracted witha sodium carbonatesolution of strength, the acidified sodiumcarbonatesolu'tion is extracted with chloroform, the chloroform extract isconcentrated to 50 cc. and allowed to stand for several hours. Theprecipitate that has separated is filtered off with suction and washedwell with' a little chloroform. The mother liquor is adsorbed on acidsilica gel After a weakly yellowish zone has been eluated when washingwith chloreform, the deep yellow zone slowly passing through the columnis cut out and eluated with a mixture of chloroform and acetone in aproportion of l0:1. The

eluate is evaporated to dryness, the residue is takenup in a mixture of10 cc. of acetone and cc. of benzene and the acetone is distilled offazeotropically. The solution is allowed to stand for several hours andthe third fraction of1.2.3.4-tetrahydro-3-carboxy-9-methyl-5-chloro-8.lO-dimethoxyanthracene-lone that has separated is filtered oif withsuction. T he filter residueis washed with ether and dried. Therefare, obtained altogether 13.2grams (=88% of the theoretical yield) of the said compound melting at218-220" .C.

8 (d5) 3 of h ester of the-formula oi "on; l oooo on i c oooctonag,"

Cl CH3 1 V COOG(OH:.)a

CH2GCOOC(CH3)3 C'HaCOOH OCHs OCHs that separates is extracted withchloroform, the chloroform extract is dried and the solvent is distilledoff. The residue istaken up in 250 cc. of glacial acetic acid and thesolution is diluted with 1500 cc. of polyphosphoric acid. The mixture isthen heated for 2 hours at 60 C. The solution turning deep red ispoured, While stirring vigorously, into much water and the reactionproduct is extracted with ether. The ether extract is freed byfiltration from black fiocculent decomposition products and exhaustivelyextracted with sodium carbonate solu tion. The ether extract is Washedwell vw'th viZter, 300 cc. of benzene are added thereto and the mixtureis dried over sodium sulfate. After elimination of the solvent thereremain 104 grams of a yellow oil that crystallizes upon trituration with200 cc. of ether. There is thus obtained a first fraction of thecompound of the formula t COOC(UHa)a 0 0 o (one COOCgCHQ amounts to 88grains (=70% of the theoretical yield). The .raw product 'thus obtainedthat can be hydrolyzed without further purification to the freedicarboxylic acid, melts between 126 C; and 130 C., whereas asamplerecrystallized from methanol melts at 131132? C.

(d 84 gra nsof the tertiary butyl ester obtained according totti aredissolved in 1 liter of methanol and (ill CH3 OOOH CODE

| OCH OGHQ O that has crystallized out is filtered off with suction, thefilter residue is washed with water and dried under reduced pressure.There are obtained 62 grams (=96% of the theoretical yield) ofdicarboxylic acid.

(d 200 milligrams of carboxy-S-chloro-S.9-dimethoxy 10 methyl 1.2.3.4tetrahydro anthracene 1- one are dissolved in 5 cc. of hot glacialacetic acid. 20 cc. of concentrated hydrochloric acid are added to thesolution and the mixture is allowed to stand for 3 hours at roomtemperature. The solution that is at first red and later on turnsyellow, from which the demethylation product has partly separated, isdiluted with water and the mixture is extracted with chloroform. Whenconcentrating the chloroform extract the 3-carboxy-S-chloro-8.9-dihydroxylO-methyll .2. 3 .4-tetrahydro-anthracenel-one separates inthe form of orange crystals. The yield amounts to 162 milligrams (=88%of the theoretical yield). After repeated recrystallization from benzenethe compound melts at 196-197 C.

I claim: 1. A compound of the formula CHaO OCHs 4 wherein R is a memberselected from the group consisting of hydrogen, carboxy, and carbalkoxythe alkyl portion of which has 1 to 4 carbon atoms, and R is a memberselected from the group consisting of carboxy and carbalkoxy the alkylportion of which has 1 to 4 carbon atoms.

2. A compound of the formula o1 CH I OOOalk 0 CH OCH; 0

wherein alk stands for alkyl having up to 4 carbon atoms.

3. A compound of the formula C1 CH C 0 0C (CH3):

C O O C (011a):

com 0011, 0

4. The compound of the formula C1 CH3 CODE 5 COOH 10 5. The compound ofthe formula CO0H 15 I OCHa 60113 \O 6. The method of making a compoundof the formula 01 CH I /R1 R2 01130 OCH O wherein R and R are selectedfrom the group consisting of carbethoxy and carbo-t-butoxy whichcomprises con tacting a first compound of the formula (JO-A 01130 (I)CH3 40 where A is a member selected from the group consisting ofchlorine, bromine, and alkoxy the alkyl portion of which has 1 to 4carbon atoms, with lithium aluminum hydride, whereby said first compoundis reduced to form an alcohol; then contacting said alcohol with amember of 5 the group consisting of phosphorus tribromide, phosphoruspentabromide, thionyl chloride, and paratoluenesulfonic acid chloride,whereby a second compound, corresponding with halides and tosylates ofsaid alcohol, is formed; then contacting said second compound with amember of the group consisting of sodium carbethoxy succinic aciddiethyl ester and sodium carbethoxy methyl malonic acid di-t-butylester, whereby a third compound, which is -a condensate of thereactants, is formed; and then contacting said third compound withpolyphosphoric acid, whereby said third compound is cyclized to form theproduct.

7. A method as in claim 6 wherein said product is contacted with adilute solution of an alkali metal hydroxide, whereby said groups R andR are hydrolyzed to carboxy groups to form a dicarboxylic acid.

8. A method as in claim 7 wherein said dicarboxylic acid is heated at atemperature above 170 0., wherebydecarboxylation occurs and amonocarboxylic acid is. formed.

References Cited in the file of this patent Muxfeldt et al.: Chem.Abst., 53, 16088, Sept. 10, 1959 (citing Abhandl, Brauuschweig. wiss.Gm, 10, 1 to 8 (1

1. A COMPOUND OF THE FORMULA
 6. THE METHOD OF MAKING A COMPOUND OF THEFORMULA